Therapy-related leukemias following treatment with drugs that target DNA toposiomerase II frequently involve translocations of the MLL gene on chromosome band 11q23. This research project will focus on functional analysis of MLL translocations, with a major focus on the MLL-CBP translocation. MLL-CBP was cloned as the MLL fusion present in patients with a t(11;16) (q23;p13). With one exception, these patients had therapy-related leukemia, and a substantial proportion presented with t-MDS. We recently developed murine model systems for the in vitro and in vivo analysis of the MLL-CBP fusion. This project involves studies to further delineate critical functions contributed by CBP to the fusion protein, to determine the functional effects of domain swapping on leukemia and pre-leukemia phenotype, and to determine the effects of the MLL-CBP fusion on hematopoietic cell lineage commitment and survival.